TRAIL decoy receptors mediate resistance of acute myeloid leukemia cells to TRAIL.

Roberta Riccioni, Luca Pasquini, Gualtiero Mariani, Ernestina Saulle, Annalisa Rossini, Daniela Diverio, Elvira Pelosi, Antonella Vitale, Anna Chierichini, Michele Cedrone, Robin Foà, Francesco Lo Coco, Cesare Peschle, Ugo Testa

Journal: Haematologica 2007;90(5):612-24

PMID: 15921376

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Abstract

BACKGROUND AND OBJECTIVES

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is regarded as a potential anticancer agent. However, many cancer cells are resistant to apoptosis induction by TRAIL. The present study was designed to evaluate the sensitivity to TRAIL-induced apoptosis in acute myeloblastic leukemias (AML).

DESIGN AND METHODS

TRAIL/TRAIL receptor (TRAIL-R) expression and sensitivity to TRAIL-mediated apoptosis were explored in 79 AML patients, including 17 patients with acute promyelocytic leukemia (APL).

RESULTS

In non-APL AML we observed frequent expression of TRAIL decoy receptors (TRAIL-R3 and TRAIL-R4), while TRAIL-R1 and TRAIL-R2 expression was restricted to AML exhibiting monocytic features. Total leukemic blasts, as well as AML colony-forming units (AML-CFU), were invariably resistant to TRAIL-mediated apoptosis. APL express membrane-bound TRAIL on their surface and exhibit a pattern of TRAIL-R expression similar to that observed in the other types of AML. Before, during and after retinoic acid treatment APL cells are TRAIL-resistant. The induction of granulocytic maturation of APL cells by retinoic acid was associated with a marked decline of TRAIL expression.

INTERPRETATION AND CONCLUSIONS

The analysis of experimental APL models (i.e., U937 cells engineered to express PML/RAR-Eo and NB4 cells) provided evidence that PML/RAR-Eo expression was associated with downmodulation of TRAIL-R1 and with resistance to TRAIL-mediated apoptosis. We suggest that AML blasts, including APL blasts, are resistant to TRAIL-mediated apoptosis, a phenomenon seemingly related to the expression of TRAIL decoy receptors on these cells. Finally, APL blasts express membrane-bound TRAIL that could confer an immunologic privilege to these cells.

Address: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.

MeSH Terms: Acute Disease, Adolescent, Adult, Antineoplastic Agents, Apoptosis, Caspase 3, Caspase 8, Cell Differentiation, Cell Membrane, Cytarabine, Drug Resistance, Neoplasm, Etoposide, Female, GPI-Linked Proteins, Granulocytes, HL-60 Cells, Humans, Hydroxyurea, Leukemia, Myeloid, Leukemia, Promyelocytic, Acute, Male, Middle Aged, Monocytes, Oncogene Proteins, Fusion, Receptors, TNF-Related Apoptosis-Inducing Ligand, Receptors, Tumor Necrosis Factor, Receptors, Tumor Necrosis Factor, Member 10c, Recombinant Fusion Proteins, Tretinoin, Tumor Cells, Cultured, Tumor Necrosis Factor Decoy Receptors, Tumor Stem Cell Assay, U937 Cells